Clinical and experimental nephrology · 2026
Imeglimin pretreatment improves survival and attenuates sepsis-associated acute kidney injury following Escherichia coli challenge in diabetic mice.
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Goto Hiroyasu, Tomita Kengo, Kuwata Koji, Mori Kazuma, Nakashima Masahiro, Nakashima Hiroyuki, Kinoshita Manabu, Oshima Naoki
Аннотация
BACKGROUND: Sepsis is a serious condition that induces systemic inflammation and multiple organ injuries, including sepsis-associated acute kidney injury (SA-AKI). Diabetes is a risk factor for SA-AKI that can worsen sepsis outcomes. We investigated whether the novel oral antihyperglycemic drug and AMP-kinase (AMPK) activator imeglimin could ameliorate SA-AKI and the survival in diabetic mice by improving the mitochondrial function.
METHODS: Male C57BLKS/J Iar -+Leprdb/+Leprdb (db/db) mice were fed imeglimin-mixed (Ime) or vehicle (Veh) foods for two weeks followed by an Escherichia coli (E. coli) challenge. Survival, kidney functions, serum cytokine, lactate and ketone levels, and the mitochondrial function were examined. To exclude the glucose-lowering effect of imeglimin on sepsis outcomes, we also studied using a streptozotocin (STZ)-induced diabetic mouse model.
RESULTS: The Ime group showed ameliorated survival rate and kidney injury after E. coli challenge compared to the Veh group in db/db and STZ mice. The Ime group showed a significantly higher p-AMPK/AMPK ratio than Veh. The mitochondrial membrane potential of tubular cells and the kidney ATP concentration improved in the Ime group of both diabetes types, although the recovery of fatty acid oxidation and changes in serum lactate and ketone levels differed between db/db and STZ mice. The level of serum IL-6 was also lower in the Ime group than the Veh group.
CONCLUSION: Imeglimin could prevent SA-AKI and increase the survival rate after E. coli challenge. The preservation of mitochondrial function via AMPK enhancement by imeglimin presumably resulted in early resolution of the metabolic deterioration due to sepsis.
METHODS: Male C57BLKS/J Iar -+Leprdb/+Leprdb (db/db) mice were fed imeglimin-mixed (Ime) or vehicle (Veh) foods for two weeks followed by an Escherichia coli (E. coli) challenge. Survival, kidney functions, serum cytokine, lactate and ketone levels, and the mitochondrial function were examined. To exclude the glucose-lowering effect of imeglimin on sepsis outcomes, we also studied using a streptozotocin (STZ)-induced diabetic mouse model.
RESULTS: The Ime group showed ameliorated survival rate and kidney injury after E. coli challenge compared to the Veh group in db/db and STZ mice. The Ime group showed a significantly higher p-AMPK/AMPK ratio than Veh. The mitochondrial membrane potential of tubular cells and the kidney ATP concentration improved in the Ime group of both diabetes types, although the recovery of fatty acid oxidation and changes in serum lactate and ketone levels differed between db/db and STZ mice. The level of serum IL-6 was also lower in the Ime group than the Veh group.
CONCLUSION: Imeglimin could prevent SA-AKI and increase the survival rate after E. coli challenge. The preservation of mitochondrial function via AMPK enhancement by imeglimin presumably resulted in early resolution of the metabolic deterioration due to sepsis.